Endocrine Responsiveness and Cellular Stress. We have identified novel signaling through the unfolded protein response (UPR) that is inifiated by an endocrine therapy-induced endoplasmic reficulum stress, with signaling further integrated through the mitochondria and nucleus. Dr. Clarke and his team will model the effects of this signaling on the function of these organelles and their respecfive roles in determining cell fate as affected by ER acfion. We will use a panel of novel cell lines, many of which we isolated [8-10,35- 42]. Inifial seed genes, e.g., API [10], BCL2 [32,33], BCL3 [49], BCLW (and other BCL2 family members), CAV1 [50], ERa [51], ERRy [10], IRF1 [27,31,52], NFKB [27,33], NPM1 [27-29], and XBP1 [27,32] will be used to initiate computational modeling of endocrine-related cell stress signals. We will extend this signaling network by including other genes known to affect endoplasmic reticulum and mitochondrial funcfion, incorporafing new targets as implicated by the functional genomics in Project 2 and the rodent studies in Project 3.